BRL-49653 BLOCKS THE LIPOLYTIC ACTIONS OF TUMOR-NECROSIS-FACTOR-ALPHA- A POTENTIAL NEW INSULIN-SENSITIZING MECHANISM FOR THIAZOLIDINEDIONES

Thiazolidinediones (TZDs) such as BRL 49653 are a class of antidiabeti c agents that are agonists for the peroxisome proliferator-activated n uclear receptor (PPAR-gamma 2). In vivo, TZDs reduce circulating level s of free fatty acids (FFAs) and ameliorate insulin resistance in indi viduals with obesity and NIDDM. Adipocyte production of TNF-alpha is p roposed to play a role in the development of insulin resistance, and b ecause BRL 49653 has been shown to antagonize some of the effects of T NF-alpha, we examined the effects of TNF-alpha and BRL 49653 on adipoc yte lipolysis. After a 24-h incubation of TNF-alpha (10 ng/ml) with 3T 3-L1 adipocytes, glycerol release increased by similar to 7-fold, and FFA release increased by similar to 44-foId. BRL 49653 (10 mu mol/l) r educed TNF-alpha-induced glycerol release by similar to 50% (P < 0.001 ) and FFA release by similar to 90% (P < 0.001). BRL 49653 also reduce d glycerol release by similar to 50% in adipocytes pretreated for 24 h with TNF-alpha. Prolonged treatment (5 days) with either BRL 49653 or another PPAR-gamma 2 agonist, 15-d-Delta-(12,14)-prostaglandin J(2) ( 15-d Delta PGJ2), blocked TNF-alpha-induced glycerol release by simila r to 100%. Catecholamine (isoproterenol)-stimulated lipolysis was unaf fected by BRL 49653 and 15-d Delta PGJ2. BRL 49653 partially blocked t he TNF-alpha-mediated reduction in protein levels of hormone-sensitive lipase and perilipin A, two proteins involved in adipocyte lipolysis. These data suggest a novel pathway that may contribute to the ability of the TZDs to reduce serum FFA and increase insulin sensitivity.